Submissions for variant NM_000059.4(BRCA2):c.7444A>G (p.Thr2482Ala)

dbSNP: rs1566241850

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775706	SCV000910121	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2482 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with Lynch syndrome (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820402	SCV000961113	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2482 of the BRCA2 protein (p.Thr2482Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 630432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000775706	SCV001188824	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-20	criteria provided, single submitter	clinical testing	The p.T2482A variant (also known as c.7444A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7444. The threonine at codon 2482 is replaced by alanine, an amino acid with similar properties. This alteration was identified in at least one patient from a cohort of 1040 individuals with advanced cancer diagnoses who underwent paired germline and tumor genetic testing (Mandelker D et al. JAMA. 2017 09;318:825-835). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001548687	SCV001768643	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 7672A>G; Observed in individuals with Lynch syndrome related cancer and/or polyps and with advanced cancer (Yurgelun 2015, Mandelker 2017); This variant is associated with the following publications: (PMID: 28873162, 25980754)
All of Us Research Program, National Institutes of Health	RCV004803203	SCV005425748	uncertain significance	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 2482 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected to be affected with Lynch syndrome (PMID: 25980754). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005407951	SCV006073971	uncertain significance	not specified	2025-04-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7444A>G (p.Thr2482Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251276 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7444A>G has been observed in individual(s) suspected of Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 630432). Based on the evidence outlined above, the variant was classified as uncertain significance.